The transcription factor HIF (Hypoxia Inducible Factor) has a central role in oxygen homeostasis. An early response to tissue hypoxia is induction of Hypoxia Inducible Factor (HIF), a basic helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentration. HIF is a heterodimer consisting of a constitutively expressed beta subunit and one of the two alpha subunits, HIFα1 and HIFα2.1 
In oxygenated (normoxic) cells, HIFα subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα is not degraded, and an active HIFα/β complex accumulates in the nucleus and activates the expression of several genes including glycolytic enzymes, glucose transporter (GLUT)-1, erythropoietin (EPO), vascular endothelial growth factor (VEGF) and adrenomedullin.1 
Thus, HIF activation is one of the prominent adaptive mechanisms associated with hypoxia/ischemia. As mentioned, HIF activation results in enhanced expression of genes which perform multiple functions to cope up with and to recover from hypoxic/ischemic conditions.2 
In oxygenated cells (normoxic), two conserved proline residues of HIFα subunits undergo hydroxylation. This reaction is catalysed by HIF prolyl-hydroxylases (PHD). Prolyl hydroxylated HIFα interacts with pVHL and rapidly gets degraded by proteasome machinery. In addition, in normoxic cells, one conserved asparagine of HIFα also undergoes hydroxylation. This reaction is catalysed by HIF asparagyl hydroxylase (FIH). Asparagyl hydroxylated HIFα can not interact with transcriptional co-activator CBP/p300.
Under hypoxic/ischemic conditions, both HIF prolyl and HIF aspargyl hydroxylase activities are drastically lowered due to limiting amount of molecular oxygen. As a result, HIFα is not destined for proteasome degradation and hence stabilized. Further, HIFα can interact with transcriptional co-activator CBP/p300. Such stabilized and transcriptionally active HIFα then forms heterodimer with HIF-beta subunit and translocates to the nucleus and bring about transactivation of HIF target genes1.
Inhibition of HIF prolyl hydroxylases and HIF asparagyl hydroxylase, thus can be a powerful approach for oxygen—independent activation of HIF. Such HIF activation by pharmacological means results in enhanced expression of genes which perform multiple functions to cope up with and to recover from hypoxic/ischemic conditions. HIF targets include genes responsible for vasomotor regulation (e.g. Adrenomedullin, eNOS, Haem Oxygrenase), energy metabolism (e.g. Glut-1, carbonic anhydrase-9), angiogenic signaling (e.g. VEGF, VEGF receptor-1) and erythropoiesis (e.g. Erythropoietin, Transferrin, transferrin receptor)1. Therefore, HIF activation can offer significant therapeutic benefits in various disease conditions such as anemia of various types and tissue injuries caused by hypoxia/ischemia in conditions like acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury, peripheral vascular diseases and transplantation of liver or kidney3,4,5,6,7,8
Anemia is characterised by decrease in normal number of red blood cells, which is generally caused by loss of blood (hemorrhage), excessive red blood cell destruction (hemolysis) or deficient red blood cell production (ineffective hematopoiesis). Since hemoglobin normally carries oxygen from the lungs to the tissues, anemia leads to hypoxia in organs. Since all human cells depend on oxygen for survival, anemia can have a wide range of clinical consequences.
Anemia occurs often in elderly, in cancer patients, particularly those receiving chemotherapy & undergoing radiation, patients with renal diseases and in a wide variety of conditions associated with chronic diseases. Frequently, the cause of anemia is reduced erythropoietin (EPO) production resulting in prevention of erythropoiesis.
Erythropoietin (EPO), a naturally occurring hormone that is produced in response to HIFα, stimulates the production of erythrocytes. EPO is normally secreted by the kidneys, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia)9.
Exogeneous administration of EPO is one of the accepted modalities of treatment of anemia particularly in chronic renal failure patients, cancer patients undergoing radiation and/or chemotherapy; however its use is limited by high cost and increased risk for thrombosis and hypertension10.
Ischemia is defined as an absolute or relative shortage of oxygen to a tissue or organ and can result from disorders such as atherosclerosis, diabetes, thromboembolisms, hypotension, etc. The heart, brain and kidney are especially sensitive to ischemic stress caused by low blood supply.
Ischemia can be an acute (sudden onset and short duration) or chronic (slow onset with long duration or frequent recurrence). Acute ischemia is often associated with regional, irreversible tissue necrosis (an infarct), whereas chronic ischemia is usually associated with transient hypoxic tissue injury. If the decrease in perfusion is prolonged or severe, however, chronic ischemia can also be associated with an infarct. Infarctions commonly occur in the spleen, kidney, lungs, brain, and heart, producing disorders such as intestinal infarction, pulmonary infarction, ischemic stroke, and myocardial infarction.
Ischemic and hypoxic disorders are a major cause of morbidity and mortality.
Currently, treatment of ischemic and hypoxic disorders is focused on relief of symptoms and treatment of causative disorders but none of these therapies directly address the tissue damage produced by the ischemia and hypoxia.
Exogenous administration of some of the HIF target genes such as erythropoietin, VEGF, adrenomedullin has shown significant functional recovery in ischemia and ischemia-reperfusion injury of heart, kidney, brain and liver.11,12,13,14 
Due to deficiencies in current treatments of anemia & diseases due to hypoxia and ischemia, there remains a need for compounds that are effective in treating anemias of different types such as anemia in elderly or anemia associated with chronic diseases or renal failure or cancer or infection or dialysis or surgery or chemotherapy and in ischemic/hypoxic disorders such as acute kidney injury, myocardial infarction, stroke, hepatic ischemia-reperfusion injury and peripheral vascular diseases.
The compounds of this invention provide a means for inhibiting HIF hydroxylases and thereby activating the HIF, which results in enhanced expression of the wide spectrum of target genes including erythropoietin (EPO), vascular endothelial growth factor (VEGF), adrenomedullin etc. and thus useful in treating various disorders including anemia of different types and conditions associated with ischemia/hypoxia.
EP 661269 discloses substituted heterocyclic carboxylic acid amides and their use as inhibitors of prolyl-4-hydroxylase and as inhibitors of collagen biosynthesis.
Additionally, various patent publications such as WO2003049686, WO2003053997, WO2004108121, WO2007146425, WO2007146438 disclose the compounds that stabilize HIFα and their use for the prevention and treatment of conditions associated with ischemia & hypoxia and EPO associated conditions like anemia and neurological disorders.
JP 5039293 discloses a various fused and substituted thiazolopyrimidine derivative or it's salt, useful as an immunomodulating agent.
International publications WO2009039321 and WO2009039322 disclose bicyclic heteroaromatic N-substituted glycine derivatives, which are antagonists of HIF prolyl hydroxylases and are useful for treating diseases benefiting from the inhibition of these enzymes like anemia.